Project Summary/Abstract Persons in the US with treated end-stage renal disease (ESRD) have an annual mortality rate of over 20% and death rates from cardiovascular disease (CVD) that are 10-100 times higher than the general population. Clinical trials to reduce traditional cardiovascular risk factors have not demonstrated significant survival benefit in dialysis. Vascular calcification is a novel and important mechanism leading to CVD morbidity and mortality in the dialysis population; however, there have been few large scale prospective studies. The overall objective of this proposal is to study novel vascular calcification risk factors for subclinical and incident CVD and gain a better understanding of the magnitude and direction of association in persons with ESRD. We will measure vascular calcification proteins, osteoprotegerin, fetuin-A and matrix gla protein, that are intricately involved in the process of calcification within the vascular beds. Our previous work and preliminary data demonstrates a significant, graded association of these proteins with aortic stiffness and mortality in those with chronic kidney disease. In this proposal, we will determine if vascular calcification factors lead to an array of subclinical measures of CVD using state of the art technology with computed tomography (CT) for coronary and valvular calcium and CT angiography as well as validated outcomes from echocardiography, pulse wave velocity and ankle brachial index. We will also be testing the association of the vascular calcification markers with adjudicated incident CVD events using validated and reliable assessments of myocardial infarction, stroke, peripheral vascular disease, mortality as well as novel assessments of arrhythmias with signal averaged electrocardiograms. This proposal is a renewal of the NIH funded study, Predictors of Atherosclerotic and Cardiovascular Risk in ESRD (PACE) study, which is a large prospective cohort study of incident dialysis participants investigating risk factors for arrhythmias and sudden death. Results from the study will provide valuable insight into the relationship of vascular calcification with subclinical and incident CVD and will form the basis for development of new diagnostic and therapeutic strategies to improve screening and treatment for CVD in ESRD.